Bicalutamide represented by the formula (I):
is reported as a useful compound having an antiandrogen activity (EP0100172-A, EP1462442-A, US2004/0044249A1, and the like), and is also an important compound currently employed for various drug applications.
Formulations of bicalutamide are provided in forms of tablets and capsules, and such formulations must be strictly administered under the standards required therefor to stably exhibit medicinal effects of the bicalutamide. Especially, as particle sizes and specific surface areas of bicalutamide crystals used for a bulk significantly affect medicinal effects and side effects, it is expected to be important to employ bicalutamide crystals having suitable particle sizes and specific surface areas. Consequently, developments of bicalutamide crystals having such suitable particle sizes and specific surface areas and methods of efficiently producing such crystals are desired.
EP1462442-A discloses a method for producing bicalutamide crystals of which shapes are regulated by dissolving bicalutamide in ethyl acetate followed by addition of heptane or the like to crystallize. The bicalutamide crystals thus obtained, however, have the particle sizes of 45.6 μm of Dp10, 90.7 μm of Dp50 and 177.6 μm of Dp90, according to the measurement results conducted by the present inventors.
US2004/0044249A1 describes a method of crystallizing bicalutamide by adding acetone into an aqueous dispersion of bicalutamide crystals in a range of dissolving the bicalutamide crystals, followed by leaving the solution standing at a room temperature. This method, however, may decrease efficiency because of the requirement of a large amount of solvent to completely dissolve bicalutamide crystals as well as decrease recovery rate due to the great volume of the solvent. Besides, since the particle sizes of crystals thus obtained are large, this method, as well as that of EP1462442-A, is not necessary the way of efficiently producing suitable bicalutamide crystals.